Summary of work: In the past year significant progress has been made in our studies of basic mechanisms of aging in primates. Our efforts to discover markers of aging have resulted in interesting findings in several areas. For example, we have found evidence that several biological parameters known to be altered by caloric restriction in monkeys may be related to longevity in humans. Specifically, reduced fasting serum insulin levels and body temperature and a slower rate of decline in serum DHEAS levels are correlated with increased longevity. Neuroimaging studies using PET and MRI have shown that, as reported in both human and rodent model systems, dopamine receptor binding is reduced in old monkeys. Also, although total brain volume does not change with age, the volume of the caudate putamen and the striatum are significantly reduced in older monkeys. We have begun studies to investigate the effects of long-term CR on these markers. These studies may have important implications for the study of cognitive and motor function decline in humans.Recent studies related to metabolic mechanisms of CR have shown that changes in insulin secretion and responsiveness to a glucose challenge are among the earliest metabolic adaptations to CR in monkeys. During the past year we have also begun studies to elucidate possible mechanisms of CR. Recent genetic studies using invertebrate model systems suggest that insulin signal transduction may relate to longevity determination in these species. We are investigating the role of insulin signaling in aging and the retardation of aging and disease by CR. Preliminary studies show that one major component of this pathway; phosphatidylinositol 3-kinase may be altered during aging and CR.